Retinitis Pigmentosa and Therapeutic Approaches: A Systematic Review

Background: Retinitis pigmentosa (RP) is a group of hereditary retinal dystrophies characterized by progressive degeneration of photoreceptor cells, which results in debilitating visual impairment. This systematic review aims to evaluate the efficacy and safety of emerging treatment modalities for RP, including gene therapy, mesenchymal-cell-based approaches, and supplementary interventions. Methods: A comprehensive search of electronic databases was conducted to identify relevant studies published up to February 2024. Studies reporting outcomes of treatment interventions for RP, including randomized controlled trials, non-randomized studies, and case series, were included. Data extraction and synthesis were performed according to predefined criteria, focusing on assessing the quality of evidence and summarizing key findings. Results: The search yielded 13 studies meeting inclusion criteria, encompassing diverse treatment modalities and study designs. Gene therapy emerged as a promising therapeutic approach, with several studies reporting favorable outcomes regarding visual function preservation and disease stabilization. Mesenchymal-cell-based therapies also demonstrated potential benefits, although evidence remains limited and heterogeneous. Supplementary interventions, including nutritional supplements and neuroprotective agents, exhibited variable efficacy, with conflicting findings across studies. Conclusions: Despite the lack of definitive curative treatments, emerging therapeutic modalities promise to slow disease progression and preserve visual function in individuals with RP. However, substantial gaps in evidence and heterogeneity in study methodologies underscore the need for further research to elucidate optimal treatment strategies, refine patient selection criteria, and enhance long-term outcomes. This systematic review provides a comprehensive synthesis of current evidence and highlights directions for future research to advance the care and management of individuals with RP.


Introduction
Retinitis pigmentosa (RP) is one of the most prevalent inherited retinal dystrophies worldwide, encompassing a group of genetically heterogeneous disorders primarily affecting the photoreceptor cells within the retina [1].It is estimated to affect more than 1.5 million patients worldwide, with varying prevalence across different populations and ethnicities [2].This condition is characterized by progressive degeneration of the photoreceptor cells, leading to debilitating visual impairment and often culminating in legal blindness in its advanced stages.The hallmark clinical features of RP typically manifest as night blindness, followed by gradual constriction of the visual field, decreased visual acuity, and, in some cases, the eventual loss of central vision.Electroretinography (ERG) often reveals reduced rod photoreceptor responses with reduced, to a lesser extent, cone photoreceptor responses, further corroborating the diagnosis.While RP can be present in isolation, it can also occur as part of syndromic disorders, such as Usher syndrome or Bardet-Biedl syndrome, or as a component of complex genetic syndromes.
The prognosis for individuals affected by RP varies widely based on genetic subtype, age of onset, and the rate of disease progression [1,2].Despite decades of research and considerable advancements in understanding the molecular mechanisms underpinning RP, efficacious treatment options still need to be discovered.Traditional management strategies have primarily focused on supportive measures to preserve existing vision and enhance visual function through low-vision aids and adaptive techniques.However, these interventions do not alter the natural course of the disease nor halt its progression [3].Given the significant burden imposed by RP on affected individuals and their families, there is an urgent need to explore novel therapeutic avenues that address the underlying pathophysiology of the disease.Recent years have witnessed increasing interest and substantial investment in developing gene-based therapies, cellular transplantation strategies, and supplementation regimens targeting retinal degenerative processes.These emerging therapeutic modalities hold promise in potentially slowing or halting disease progression, thereby offering hope for preserving vision and improving the quality of life for individuals living with RP [4].
In this systematic review, we aim to comprehensively evaluate the current landscape of treatment modalities for RP, with a particular focus on gene therapy, mesenchymalcell-based approaches, and supplementary interventions.Through a meticulous synthesis of existing literature and critical appraisal of clinical evidence, we endeavor to provide insights into these therapeutic interventions' efficacy, safety, and prospects in managing RP.Such an appraisal is essential for informing clinical decision making, guiding research priorities, and ultimately advancing the care and outcomes for individuals affected with this debilitating retinal disorder.

Materials and Methods
A systematic review was performed to determine the current therapeutic approaches evaluated by trials in treating patients with retinitis pigmentosa.
The review followed the guidelines established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), which provide a framework for transparent and comprehensive reporting of systematic reviews.
To identify relevant articles, we conducted a systematic literature search from the inception in 1946 to 20 February 2024 using a controlled vocabulary and specific keywords related to "retinitis pigmentosa", "mesenchymal", "mesenchymal stem cells", "stem cell transplantation", "intravitreal", "intravitreal therapy", "gene therapy", "gene vectors", "surgical approaches", and "clinical trials".The search was conducted in electronic databases such as Ovid Medline, Embase (Ovid), the Cochrane Register of Controlled Trials, and the Cochrane Database of Systematic Reviews.The "Rayyan" software (version 2022, Cambridge, MA, USA, 2022) was used as an automation tool to select articles [5].
This process allowed us to ensure complete coverage of all available literature.The complete search strategy is given in Appendix A.
After compiling the electronic article list, two reviewers (O.G. and A.L.R.) independently evaluated all the abstracts one by one and identified the articles that met the inclusion criteria.These criteria included all the studies that evaluated the efficacy of any therapeutic approaches and clinical outcomes for patients with retinitis pigmentosa.
Exclusion criteria were review studies, pilot studies, case series, case reports, photo essays, expert opinions, and studies written in languages other than English.Studies conducted on animal eyes and cadavers were also excluded.No unpublished data were requested from the corresponding authors of the selected articles; the analysis was conducted solely based on available published information.A consensus was reached in case of disagreement among reviewers, and an expert reviewer (F.C.) was consulted if necessary to provide additional expertise.The determining reasons for inclusion or exclusion of the full-text reviewed articles are summarized in Appendix B.
The 2011 Oxford Centre for Evidence-Based Medicine (OCEBM) guidelines [6] were followed to assess the strength of evidence.These recommendations provide a methodological framework to evaluate the reliability and validity of evidence in medical research.The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system [7], a tool created to assess the integrity of evidence and facilitate the formulation of recommendations, was used to determine the quality of evidence.
In summary, our systematic review strictly followed the methodologies outlined in the PRISMA guidelines.It adopted a comprehensive search strategy to identify relevant studies, clearly delineated inclusion and exclusion criteria, and used established criteria to assess the level and quality of evidence.
Figure 1 summarizes the research approach applied in this systematic review within a flowchart.
Exclusion criteria were review studies, pilot studies, case series, case reports, pho essays, expert opinions, and studies written in languages other than English.Stud conducted on animal eyes and cadavers were also excluded.No unpublished data we requested from the corresponding authors of the selected articles; the analysis w conducted solely based on available published information.A consensus was reached case of disagreement among reviewers, and an expert reviewer (F.C.) was consulted necessary to provide additional expertise.The determining reasons for inclusion exclusion of the full-text reviewed articles are summarized in Appendix B.
The 2011 Oxford Centre for Evidence-Based Medicine (OCEBM) guidelines [6] we followed to assess the strength of evidence.These recommendations provide methodological framework to evaluate the reliability and validity of evidence in medi research.The Grading of Recommendations Assessment, Development, and Evaluati (GRADE) system [7], a tool created to assess the integrity of evidence and facilitate t formulation of recommendations, was used to determine the quality of evidence.
In summary, our systematic review strictly followed the methodologies outlined the PRISMA guidelines.It adopted a comprehensive search strategy to identify releva studies, clearly delineated inclusion and exclusion criteria, and used established crite to assess the level and quality of evidence.
Figure 1 summarizes the research approach applied in this systematic review with a flowchart.
Gender distribution was equally represented across the studies, ensuring a balanced sample.On average, approximately 50% of participants were male, and 50% were female, reflecting the inclusivity of the research.Regarding the severity of retinitis pigmentosa (RP) among participants, most studies included individuals with advanced RP or RP complicated by macular edema.However, some trials incorporated patients with varying degrees of disease severity, from early-stage to advanced RP [8,9].
A comprehensive data synthesis was unavailable due to the diversity of the available data and differences in research designs.
Studies included are hereby subdivided in the following sections and summarized in Table 1.

Mesenchymal Stem Cells
In a study by Zhao et al. (2020) [8], 32 adult patients (64 eyes) underwent intravenous infusion of human umbilical cord MSCs (UCMSCs) with a follow-up period of 12 months.The treatment involved a single injection of 10 8 UCMSCs, and evaluations included safety assessments, central macular thickness (CMT), visual field sensitivity, best-corrected visual acuity (BCVA), flash visual evoked potential (FVEP), and the NEI-VFQ-25 questionnaire.The results indicated a good tolerance of UCMSC infusion, with no adverse effects observed.Although there were non-significant changes in macular thickness and BCVA, the NEI-VFQ-25 scores significantly improved three months posttreatment (p < 0.05), suggesting short-term therapeutic effects mainly within the initial three months.
In another study by Zhao et al. ( 2021) [9], 20 adult patients (40 eyes) with RP complicated by macular edema were enrolled to compare the efficacy of intravenous UCMSC infusion with modified sub-Tenon's capsule injection of triamcinolone acetonide (TA).The follow-up duration was six months.Both treatments demonstrated safety, with no severe adverse effects observed.While TA rapidly reduced CMT in the short term, UCMSC infusion offered longer-lasting benefits, with a more significant reduction in CMT observed at six months (p < 0.05).Additionally, UCMSCs showed a significantly greater FVEP amplitude growth rate than TA at six months (p < 0.05), indicating superior therapeutic potential in improving visual function.Kahraman et al. (2020) [10] conducted a study involving 82 RP patients (124 eyes) who underwent a surgical procedure to inject 5 million UCMSCs into the suprachoroidal area.This intervention resulted in statistically significant improvements in BCVA and visual field (VF) tests over a 6-month follow-up period (p < 0.05).Additionally, multifocal electroretinography (mfERG) recordings showed significant improvements in the amplitudes of P1 waves in the central areas, indicating positive effects on retinal function.
Ozmert et al. ( 2023) [11] investigated the effects of sub-Tenon WJ-MSC injection, Magnovision stimulation, and their combination in 80 RP patients (130 eyes).The study found that FAF-field delta changes were 0.39 mm 2 in the WJ-MSC-only group, 1.50 mm 2 in the Magnovision-only group, 0.07 mm 2 in the combined management group, and 12.04 mm 2 in the control group (p < 0.05).
Tuekprakhon et al. (2021) [12] conducted a prospective, open-label, non-randomized phase I clinical trial involving 14 adult RP patients who underwent intravitreal injection of autologous BM-MSCs aspirated from the patient posterior iliac crest.The participants were divided into three intervention groups based on the quantity of MSCs injected: Group 1 received 1 × 10 6 cells, Group 2 received 5 × 10 6 cells, and Group 3 received 1 × 10 7 cells.Group 1 showed the most significant improvement compared to the fellow eye, with statistically significant improvements observed at months 7 and 8. Group 3 displayed immediate significant BCVA improvement at month 1, returning to baseline by month 6.Additionally, most participants reported subjective improvements in quality of life.
A study by Limoli et al. (2020) [13] involved 25 RP patients who underwent an autograft of mesenchymal cells, fat cells, and platelet-rich plasma (PRP) using LRRT.The patients were subdivided based on central retinal thickness, and improvements in BCVA were observed in both groups, with statistically significant improvements noted in Group A (p < 0.05).

Gene Therapy
Kapetanovic et al. (2020) [14] enrolled 18 patients with X-linked retinitis pigmentosa (RP) caused by mutations in RPGR.The treatment involved the delivery of increasing concentrations of a codon-optimized AAV2 serotype 8 vectors (AAV8.coRPGR)into the subretinal space via a two-step injection.The primary safety endpoint was the incidence of dose-limiting toxicities and treatment-emergent adverse events over 24 months, with secondary endpoints including changes in retinal sensitivity, best-corrected visual acuity (BCVA), SD-OCT, and autofluorescence over the same period.The study revealed a dose-response effect across the trial cohorts regarding gains in visual function in treated eyes.Patients who received mid-dose injections of AAV8.coRPGR showed gains in retinal sensitivity and reversal of some visual field loss by month 1, with sustained treatment effects observed through to the 6-month follow-up.All patients reported subjective improvements in visual clarity and an increase in the field of vision within one month of follow-up.However, early cohort patients with advanced retinal degeneration showed no noticeable gains in visual function at low vector doses, although visual acuity returned to baseline levels by three months postsurgery.
In the study by Albert M. Maguire et al. (2021) [15], which involved 29 patients with RPE65 mutation-associated inherited retinal dystrophy (IRD), gene augmentation therapy was administered using the recombinant adeno-associated viral vector Voretigene Neparvovec.Patients were randomized into original intervention and delayed intervention control groups, with assessments conducted at various intervals over five years.The intervention group received 1.5 × 10 11 vg of VN in each eye, while the control group underwent delayed intervention after one year.The results showed consistent but insignificant improvements in ambulatory navigation, light sensitivity, and visual field over 3 to 4 years compared to baseline in both groups.No significant differences were observed between the two groups regarding efficacy.Safety assessments revealed no product-related serious adverse events, although one delayed intervention group patient experienced loss of foveal function attributed to the administration procedure.

Docoexhanoic Acid
The DHAX trial by Dennis R. Hoffman et al. (2015) [16], a single-site, placebocontrolled, randomized clinical trial involving 51 patients with X-linked retinitis pigmentosa (XLRP), comprised 29 treated and 22 placebo groups.The trial investigated the efficacy of oral docosahexaenoic acid (DHA) supplementation over four years.The treatment group received 30 mg DHA/kg/d, while the placebo group received a placebo.Visual outcomes were measured annually, and red blood cell (RBC) DHA levels were determined every six months.Oral DHA supplementation significantly increased mean RBC-DHA levels by 4-fold over placebo (p < 0.0001).While no significant group differences were found for visual acuity, shape discrimination, or fundus appearance, DHA supplementation showed substantial reductions in the yearly progression rates for dark-adapted thresholds and visual field sensitivity in various regions (p = 0.06 to <0.0001).Visual field sensitivity decline rates depended on RBC-DHA levels (p = 0.046 to <0.0001).
Similarly, a previous trial by Dennis R. Hoffman et al. (2003) [17] was a 4-year prospective randomized clinical trial that enrolled male patients with XLRP (mean age = 16 years; range = 4-38 years) who received either DHA (400 mg/d) or placebo.The study assessed red blood cell (RBC)-DHA concentrations every six months and recorded full-field cone electroretinograms (ERGs), visual acuity, dark adaptation, visual fields, rod ERGs, and fundus photos annually.The +DHA group exhibited a 2.5-fold increase in RBC-DHA levels over placebo (70 vs. 28 mg DHA/L).While there was no significant difference in the rate of cone ERG functional loss between groups, DHA supplementation was beneficial in reducing rod ERG functional loss in patients aged < 12 years (p = 0.040) and preserving cone ERG function in patients ≥ 12 years (p = 0.038).[18] conducted a multicenter, phase II, prospective, interventional, placebo-controlled, double-masked randomized clinical trial involving 90 male and female patients with autosomal dominant retinitis pigmentosa (AD-RP).Participants were randomized to receive either oral valproic acid (VPA) at doses ranging from 500 mg to 1000 mg daily (n = 46) or placebo (n = 44) for 12 months.Follow-up visits were scheduled at 8, 26, 39, 52, and 65 weeks.The primary outcome measure was the change in kinetic perimetry (KP) visual field area (VFA) between baseline and week 52, assessed by the III4e isopter, with greater sensitivity indicating improvement.

Birch et al. (2018)
The study did not meet its primary endpoint, as there was no significant change in visual field area between the VPA and placebo groups at 12 months.Furthermore, the two groups observed no substantial improvement in the secondary outcome measures.Consequently, the study concluded no support for using valproic acid to improve visual function in patients with AD-RP.
3.6.Oral QLT091001 Scholl et al. (2015) [19] investigated the effects of oral QLT091001 in 18 patients with retinitis pigmentosa (RP) resulting from mutations in the RPE65 or LRAT genes, aged 5 to 65 years.After a 7-day course of QLT091001, ocular examinations revealed promising outcomes.Within two months of treatment, 44% of participants experienced a 20% increase in the functional retinal area, with 22% showing a 40% increase.Additionally, 67% of patients demonstrated a 5-letter increase in visual acuity, with 28% experiencing a 10-letter increase.A significant difference was observed in the length of the outer segment layer between treatment responders (average of 11.7 µm) and non-responders (average of 3.5 µm), indicating a positive treatment effect (p = 0.02).These findings highlight the potential efficacy of oral QLT091001 in improving visual function in RP patients with RPE65 or LRAT mutations, alongside its acceptable safety profile.[20] enrolled 29 patients grappling with hereditary retinal degeneration who received the Retina Implant Alpha IMS.Over a 1-year follow-up period, noteworthy outcomes were observed: 72% of participants exhibited enhancements in their daily activities and mobility, indicating a substantial improvement in their quality of life.Moreover, as much as 86% reported improved visual acuity and object recognition, showcasing the transformative potential of the implant (p < 0.05).Participants demonstrated significant improvements in detecting, localizing, and recognizing shapes and objects with the implant activated (p < 0.05).Despite initial challenges, 86% showed remarkable progress in light perception with the implant, underscoring its efficacy in restoring this critical visual function (p < 0.05).Management of adverse events ensured the safety and well-being of all participants throughout the study period, and no significant adverse events were reported.

Discussion
In RP, where clinical trials have explored various therapeutic strategies, our systematic review tried to consolidate all significant trials, providing valuable insights into their potential efficacy and challenges [21][22][23][24].
Gene therapy, exemplified by voretigene neparvovec (Luxturna), resulted in the most promising avenue for improving visual function and slowing RP progression [14,15].Similarly, CRISPR/Cas9 gene editing and RNA interference hold promise for targeted treatment strategies tailored to specific genetic mutations associated with RP in humans, even though only animal-model-based studies hold validated scientific results for now [25][26][27][28].
Neuroprotective agents, such as valproic acid (VPA), have shown potential in preclinical studies by modulating neuroinflammation and promoting neuronal survival [38].However, clinical trials evaluating VPA in RP patients have yielded conflicting results, necessitating further investigation [18].
Another possibility to treat RP patients is the implantation of a retinal prosthesis [48][49][50].Despite the promising advancements in retinal prostheses, each device comes with specific benefits and drawbacks [51].The long-term effects, safety, and durability of these devices remain uncertain.Additionally, financial constraints and a shift in focus towards visual cortical implants have led to the discontinuation of production by leading companies such as ARGUS II.This shift is primarily due to limited resources and the relatively small patient population that qualifies for retinal prostheses compared to visual cortical implants [52].
The pool of eligible candidates is further narrowed by the need for patients to be both physically and psychologically fit for surgery and postimplant rehabilitation [53].The vision provided by retinal prostheses is notably different from natural vision, requiring patients to have a strong support system, a comprehensive understanding of expected outcomes, and additional training and practice to optimize results.Furthermore, patients often need to travel significant distances for surgery, frequently out of state, and stay away from home for extended periods during the pre-and postsurgical phases [54].
As more research is conducted, the impact of these devices once they are commercially available remains uncertain.Social determinants of health (SDOHs) may hinder low-resource patients with retinitis pigmentosa (RP) from accessing these technologies.Although there are a few studies indicating a higher prevalence of RP in specific marginalized groups, cost and availability pose significant barriers for patients needing this equipment.Numerous challenges must be addressed before these devices can become commercially viable, including a thorough analysis of financial implications to ensure equitable access to care.Moreover, there is limited research on the long-term maintenance costs of these devices, and some have been discontinued while still implanted in patients [55].
The promising outcomes from studies on retinal prostheses have spurred interest in their potential applications for other vision-threatening conditions.The ORION II device by Vivani Medical, Inc. is currently being evaluated for its effectiveness in restoring vision in patients with glaucoma, diabetic retinopathy, optic nerve injuries, cancer, and trauma.Similarly, the PRIMA device and IMTC's HARP4k Retinal Prosthesis System are being studied for their potential in treating diseases that cause photoreceptor degeneration, particularly advanced atrophic dry age-related macular degeneration [56].The NR600 and BVA devices have shown promise for patients with RP and age-related macular degeneration, while the ICVP system is being investigated for its use in cases of ocular injuries, optic nerve diseases, photoreceptor degeneration, and blindness [57].
Despite these advancements, translating experimental treatments into clinical practice remains challenging.Long-term safety and efficacy data, optimized delivery methods, and consideration of RP's genetic heterogeneity are needed [58].Furthermore, the high cost of gene-and cell-based therapies presents economic barriers to widespread adoption.

Conclusions
In conclusion, while significant progress has been made in understanding and treating RP, further research is needed to elucidate optimal treatment modalities and ensure patient accessibility.By addressing these challenges through interdisciplinary collaboration and technological advances, effective treatments for RP may become a reality, offering hope to those affected by this debilitating disease.

Figure 1 .
Figure 1.Flowchart of the literature search and selection according to Preferred Reporting Items Systematic Reviews and Meta-Analyses (PRISMA).* Consider, if feasible to do so, reporting

Figure 1 .
Figure 1.Flowchart of the literature search and selection according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).* Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). ** If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.

Table 1 .
Summary of Included Studies and Salient Features.